Exploring the benefits: experimental insights on the effects of LIM and cysteine-rich domains 1 (LMCD1) reduction on cardiac hypertrophy
L Kilian, S Martini, J Voran, A Kliesow-Remes, O Mueller, D FrankAbstract
Background
Pathological left ventricular hypertrophy (LVH) is a major contributor to heart failure and cardiac mortality, commonly resulting from arterial hypertension and aortic stenosis. The LIM and cysteine-rich domains 1 protein (LMCD1) has been shown to be upregulated in both patients and experimental models of maladaptive cardiac hypertrophy. Previous research indicates that overexpression of LMCD1 promotes hypertrophy in vitro in isolated neonatal rat ventricular cardiomyocytes (NRVCM) and in vivo in mice, while its downregulation attenuates hypertrophic gene expression in vitro. However, the precise role of LMCD1 in cardiac remodeling remains poorly understood and the effects of LMCD1-reduction in vivo — although potentially beneficial have not been studied previously.
Purpose
The objective of our research is to elucidate the function of LMCD1 in hypertrophic cardiac remodeling and to explore the potential of LMCD1 downregulation in vivo.
Methods
We used mice with heart-specific knockdown of LMCD1 and employed two in vivo models of pathological cardiac hypertrophy: 1) a late-stage model with severely reduced heart function (HFrEF) induced by transverse aortic constriction (TAC) and 2) an early-stage model with preserved heart function (HFpEF) induced by neurohumoral stimulation using angiotensin II (AngII). Additionally, we conducted in vitro experiments using NRVCM with induced LMCD1 up- or downregulation and neurohumoral hypertrophic stimulation, and performed transcriptomics, proteomics and metabolic analyses.
Results
The results demonstrate that LMCD1 downregulation significantly mitigated the TAC-induced decline in heart function, the dilatation of the left ventricle and the development of fibrosis observed in late-stage hypertrophy, as well as preventing strong activation of maladaptive gene expression. Notably, the LMCD1-knockdown mice maintain a significantly higher ejection fraction than wild-type mice following TAC. Furthermore, LMCD1 downregulation attenuated AngII-induced thickening of the left ventricular walls, the reduction of the left ventricular inner diameter as well as the initiation of fetal gene expression re-activation observed in early-stage hypertrophy. In addition, the findings indicate that LMCD1 upregulation in NRVCM is associated with mitochondrial dysfunction. However, the data reveals that downregulation of LMCD1 can sustain mitochondria function by attenuating the neurohumorally-induced maladaptive metabolic shift from fatty acid oxidation (FAO) to glycolysis, a hallmark of pathological hypertrophic remodeling.
Conclusions
Taken together, our study highlights significant protective effects of LMCD1 downregulation in maladaptive cardiac hypertrophic remodeling, and provides first insights into the underlying mechanisms, including metabolic changes. The modulation of LMCD1 presents a potential therapeutic target for mitigating the development and progression of cardiac hypertrophy.